Related Experiment Videos
Cyclosporin suppresses transplant arteriosclerosis in the aorta-allografted, cholesterol-clamped rabbit. Suppression
H O Andersen1, G Madsen, B G Nordestgaard
1Department of Clinical Biochemistry, Rigshospitalet, Copenhagen O, Denmark.
Abstract:
The immunosuppressant cyclosporin has been suggested to aggravate as well as retard the development of transplant arteriosclerosis, the major long-term problem for patients with heart transplants. We examined the effect of human therapeutic levels of blood cyclosporin on the development of experimental transplant arteriosclerosis. The thoracic aorta from one rabbit was transplanted as an end-to-side bypass on the abdominal aorta of another rabbit, and plasma cholesterol was clamped at 5 to 7 mmol/L. Cyclosporin markedly suppressed the severity of transplant arteriosclerosis, judged both biochemically and histologically: cholesterol content in aortic transplants was reduced by 70% and 80% after 10 days and 20 days of cholesterol feeding, respectively (both comparisons, P < .01), and after 20 days of cholesterol feeding myointimal proliferation was totally inhibited in grafts from cyclosporin-treated animals, judged from maximal intimal thickness and intimal area on cross sections of grafts (both comparisons, P < .05). In another group of non-cholesterol-fed, aorta-transplanted rabbits, cyclosporin reduced by 90% (P < .01) an otherwise markedly increased permeability to low-density lipoprotein in transplanted aortas. These results suggest that cyclosporin causes a substantial decrease in the severity of transplant arteriosclerosis and that this effect is mediated at least partly via a large decrease in aortic lipoprotein permeability.
Insights
Cyclosporin significantly reduces transplant arteriosclerosis in rabbits by inhibiting myointimal proliferation and decreasing aortic permeability to low-density lipoprotein. This immunosuppressant offers a potential therapeutic benefit for heart transplant recipients.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Pharmacology
Background:
- Transplant arteriosclerosis is a major long-term complication following heart transplantation.
- The role of the immunosuppressant cyclosporin in transplant arteriosclerosis is controversial, with suggestions of both aggravation and retardation.
- Understanding cyclosporin's precise effect is crucial for managing heart transplant outcomes.
Purpose of the Study:
- To investigate the effect of human therapeutic levels of cyclosporin on experimental transplant arteriosclerosis.
- To determine if cyclosporin influences the development of arteriosclerosis in aortic transplants.
- To elucidate the mechanisms underlying cyclosporin's impact on transplant arteriosclerosis.
Main Methods:
- A rabbit model of aortic transplantation was utilized.
- Plasma cholesterol levels were maintained at 5-7 mmol/L in hyperlipidemic groups.
- Cyclosporin was administered at human therapeutic levels.
- Biochemical and histological assessments quantified transplant arteriosclerosis severity.
- Low-density lipoprotein permeability in transplanted aortas was measured.
Main Results:
- Cyclosporin markedly suppressed transplant arteriosclerosis severity.
- Cholesterol content in aortic transplants was reduced by 70% (10 days) and 80% (20 days) in cyclosporin-treated rabbits (P < .01).
- Myointimal proliferation was completely inhibited after 20 days of cholesterol feeding in cyclosporin-treated animals (P < .05).
- Cyclosporin reduced aortic permeability to low-density lipoprotein by 90% (P < .01) in non-cholesterol-fed rabbits.
Conclusions:
- Cyclosporin significantly decreases the severity of transplant arteriosclerosis.
- The protective effect of cyclosporin appears to be mediated, in part, by reducing aortic lipoprotein permeability.
- These findings suggest a beneficial role for cyclosporin in preventing transplant arteriosclerosis in heart transplant patients.